the EU commission publishing a MDR/ IVDR rolling plan, providing timelines and status overview for the transition period, with attention for common specifications for any of the groups of products listed in Annex XVI of the MDR and the clinical evaluation regarding safety, and designated expert panels tasked with the delivery of opinions on the clinical evaluation of high-risk devices (Q3/ Q4 2019),

we can expect a revised version of ISO 14155, with (probably) some interesting additions such as more attention for the inter-relationship with device risk management procedures, and the product developmental stages in relation to the different types of pre- and post-market clinical investigations,

The Implant Files touched upon one of the toughest dilemma’s designing a clinical study: How long do patients treated with a medical device need to be followed in a clinical study before one can say the device is safe and performing? Patient follow-up can have an enormous impact on the duration of your study, and the tendency is to keep it as short as possible; the shorter your study is, the sooner you will have the results, and thereby your publication or market approval. However, what is required, desirable, and even possible strongly depends on the purpose of the study and the medical device involved.

Besides the sample size and enrolment rate, patient follow-up can have a significant impact on the duration of your trial: imagine the length of a clinical study with an implantable device that is supposed to function for the rest of your life …, but when a study concerns a pre-market study to show safety and performance or efficacy, patient follow-up has to be long enough to prove (together with other existing data) safety and performance, while being short enough to bring the concerning device to market as soon as possible. So the golden question is

How long is long enough?

Treatment duration

Some devices are meant to be used for a short lasting period, so the required patient follow-up duration will be relatively short (or even non-existing for certain diagnostic devices). For example, examining the safety and performance of a new dialyzer during a hemodialysis session of ~4 hours, depending on your exact study objectives and the status of the concerning patients, generally needs a patient follow-up of 1 day. When the treatment, however, involves surgery and/ or general anesthesia it becomes a different story.

Surgery

Device effects may be clear within few days, but when surgery is involved and/ or the application of the device requires general anesthesia (especially when the current standard of care or alternative treatments do not), you also need to take into account the effects of general anesthesia, which are known to last for several months especially in the elderly. Thereby prolonging of the patient follow-up in your clinical study with several months, with a minimum of 30-days after the intervention.

Implantables

The situation becomes even more complex when implantable devices are involved that are supposed to function for several years. As said above: imagine the duration (and cost) of a clinical study where patients are to be followed for the rest of their life’s … By the time you collected the safety and performance data, the concerning device will be outdated. Therefore typically acceleration testing, modelling techniques, and clinical data from comparable devices are used to get a reasonable idea of long term safety and performance. That such is not always good enough has become clear in the last few decades: Possible deleterious effects of mesh and metal hips implants became only visible after several years after implantation. Which is exactly why MEDDEV 2.7/1 Rev 4 and 2.12-1, and from 2020 on also the MDR, require a much more solid Post-Market Clinical Follow (PMCF) program for the higher risk class of devices and implantables.

Post-market studies

Determining the right patient follow-up duration for a post-market clinical study, so once the device is on the market, tends to lead to even more discussion than for a pre-market study. Besides device durability, a wider range of study objectives other than ‘just’ safety and performance start weighing in, as well as the type of patient involved, but also in a post-market setting one will want to have the study results as fast as possible.

Clinical evidence gap

When, however, you need to perform a PMCF study because the (pre-market) clinical evaluation indicated, for example, there is an uncertainty on long term clinical safety or performance, it is pretty clear that patient follow-up needs to be substantially longer than for the existing data supporting the safety and performance claims at market release. Still the question remains ‘how long is long enough’ and the factors mentioned above apply. Currently I am involved in several post-market clinical follow-up studies following patients for 3 to 5 years after the device was implanted. This is pretty long considering the standard product life cycle is 18 to 24 months, but still may not be long enough for a device that is supposed to last for more than 10 years. It is not for nothing that the FDA recently required an extension of the follow-up period from 3 to 5 years for women who received the Essure birth control devices.

Patient outcomes

Besides data on safety and performance, post-market medical device studies often aim to collect clinical data on patient outcomes due to the fact that in the pre-market setting clinical evidence collection tends to focus on device performance, especially in Europe, and evidence with respect to efficacy or patient benefits often is indirect. Clinical outcomes, such as a reduced probability of mortality, morbidity, and enhanced Quality of Life, however, add yet another complicating factor, since besides the study objective and the type of device also the type of patient involved needs to be taken into account: A clinical study aiming to show the impact on patient survival with a device that has been shown to effectively destroy cancer cells, for example, will require a much longer follow-up period in patients with prostate cancer than in patients with pancreatic cancer, simply because the survival rates are so very different.

Conclusion

In short, selecting the right patient follow-up duration in your medical device study is not an easy process. The general tendency is to keep the study duration as short as possible, but different from medicinal products, the process of determining the minimal follow-up duration is affected by a complex interplay of regulatory requirements, study objective(s) and endpoints, as well as the type of medical device and patients involved.

Feel free reaching out in case you require support developping your medical device study. You can reach me through the ACS website or the information displayed in the right upper hand corner.

One of the topics discussed during the Medical Device Clinical Trial Seminar in Taipei, was the current medical device clinical trial environment in Europe and how that is evolving. A short version of my presentation, you can find on SlideShare using the following link:

In brief, there are a few key aspects that need to be taken into account when involved in the development and execution of clinical studies with medical devices in Europe, and starting with some of the

Definitions

What is new in Rev 4 of MEDDEV 2.7/1 are the definitions of clinical data, and especially clinical use, i.e. meaning use of a medical device in a living human subject, including devices without direct contact with a patient. In other words this includes a machine that ensures a continuous fluid flow rate to help raising the temperature of a body cavity.

Also new is the clarification of what is sufficient clinical evidence, i.e. data that are adequate in amount as well as quality: During a clinical evaluation the evaluator needs to take into account sample size as well as the type of trials and the regulations that were followed when the data were collected.

The state of the art is also a newly introduced term, and is relevant when evaluating or designing (a) clinical stud(y)ies as that will tell you what therapy to compare the new treatment with.

Further key definitions concern the ISO 14155 definition of a clinical investigation:

any systematic investigation in one or more human subjects, undertaken to assess the safety or performance of a medical device

which to me means that any trial on safety or performance is included regardless whether it is pre or post-market. The difference being that a pre-market study is a study conducted with non-CE marked devices, or CE marked devices used outside the intended use, and a post-market study a study after CE mark and with the device used according to the IFU, and a PMCF study a post-market study looking to answer specific questions on safety or performance.

Clinical evidence gaps

Under Rev 4 of the MEDDEV 2.7/1 there are 2 scenarios where the clinical evaluation may indicate you have a gap in your clinical evidence and a clinical study is needed:

When there is insufficient qualitative data to verify that the device meets ER’s 1,3,and 6, and you need a classic Clinical Investigation, or

when there are unanswered questions regarding safety and performance, for example on long-term performance, and you need a Post Market Clinical Follow-Up Study.

MEDDEV 2.7/1 Rev 4 indicates a pre-market Clinical Investigation is needed when your data are insufficient in quantity (it even has a table with an indication on required numbers for safety) and/ or the data have not been collected in a methodological and scientifically sound manner and/ or in compliance with standards, such as ISO 14155, and it is stressed that incompliant studies should not be used for demonstration of safety and/ or performance of the device. Typically a pre-market study is indicated to be required for implantable and high risk devices, but also for new technologies AND class I and II devices with clinical evidence gaps.

MEDDEV 2.12-2 specifies that a PMCF study generally is required for high risk devices and in case of rare diseases (for the latter the amount of clinical data is often low), but also when patient follow-up in the pre-market study/ ies is not in line with the expected product life time, think implantables such as vaginal meshes for example, or when the CE mark was based on equivalence.

EU Clinical Study Regulatory environment

As mentioned also in previous posts, the regulatory environment for clinical studies in Europe is complex and changing. Some of the directives have already been mentioned above, but at a European level we are currently dealing with MDD, the Declaration of Helsinki, ISO 14155, the different MEDDEV’s, and the different local regulations. The variations in the latter, especially for post-market studies, can make it hard to ensure international studies are run in compliance with the applicable regulations.

The upcoming MDR will make a difference in that respect, as that concerns a regulation to be implemented 1:1 in the local law, it pays much more attention to clinical investigations (count of the word investigation shows a 5-fold increase!), and it requires basically all clinical studies to follow ISO 14155. And mind you, the MDR specifies that also clinical studies not performed as part of the clinical evaluation shall comply with the general basics of good clinical practice’s, so not just the pre-market and post-market clinical investigations.

Study document requirements

So what is generally speaking needed when you are planning to do a clinical study?

Although different in the details and depending on whether it concerns a pre-market of post-market, interventional or observational study, the basics are always the same.

One always needs a protocol, an Informed Consent (also for registries!), regulatory approvals (EC and CA as applicable), a final report, and AE reporting.

Differences between pre- and post-market studies can include for example the need for an Investigator’s Brochure or an IFU, SAE or U(S)ADE expedited reporting, and the need for a study or a liability insurance for a pre-market study or a post-market observational study respectively. From experience I know, however, that the variations are disappearing, and Ethics Committee’s more and more have similar requirements for a pre- and post-market studies regardless whether the latter are observational or not.

Study endpoints and design

Due to variations in medical devices, their intended use, mode of action, and users, designing the right medical device clinical study requires a tailor-made approach for each product:

Measuring safety or undesirable side effects, concerns a relatively clear endpoint as that is all about the collection of Adverse Events, the type, number, severity, and duration. The main item that typically leads to discussion, concerns the sample size; In other words what defines safe, or to what degree are certain device related events acceptable? The table in MEDDEV 2.7/1 provides some guidance in that respect, but typically the focus is to try and capture the serious device related adverse events, so those that relate to the use of the device and led to an injury that is life-threatening, resulted in permanent damage to the body, or required an intervention to prevent this from happening.

The performance endpoint varies a lot with the device involved. Key is that the device must achieve the performances as intended or claimed by the manufacturer, which translates to different study endpoints for a pacemaker, hyperthermic perfusion system, and a dialyzer: The data on the pacemaker for example may have to show that it adequately monitors the heart rate and effectively stimulates the heart when needed, whereas the data of the hyperthermic perfusion system may only need to show that it regulates the rinsing fluid temperature within certain margins.

The effect on the patient also being more clear for one treatment than the other, because performance is not always the same as efficacy: This is where the patient benefit comes into the picture since

benefits are about a positive impact on clinical outcomes, such as a reduced probability of mortality, morbidity, and enhanced Quality of Life, and if anything is claimed by the manufacturer in this respect, clinical data is needed to substantiate the claim.

And then there is the device effect duration to consider: how long do you need to follow a patient before deciding the device is performing as intended? The last in my blog post series regarding clinical evidence dilemma’s will also address this, but the hyperthermic perfusion system and the dialyses can focus on sessions ranging from 2-4 hours, whereas a pacemaker is supposed to perform for 8-10 years! By the time you have collected the clinical data on the pacemaker, the device(model) will be outdated, so typically you extrapolate data or use long-term data from comparable products, and under the current MEDDEV 2.7/1 you will need to do a PMCF study to confirm long-term safety and performance.

Due to the variety in medical devices, the above examples only give an indication of the elements that need to be considered when developing a medical device study and the challenges that come with it, and then I have not addressed design aspects like when you need a RCT or when a single arm study might suffice.

Study design

Aspects for consideration when determining the study design include:

Gaps: Is there a gap in your clinical evidence and what is that? Do you need a study comparing your devices performance versus the State of the Art, then a RCT will be needed, a study confirming long-term device performance can be set-up as a single arm observational study.

Standards: before designing a clinical study, one should verify whether there are any other than the general standards you need to comply with and whether that dictates a certain design. In case of IOL’s for example there is the ISO 11979 that describes pretty much when to do, what type of clinical study, including the sample size.

Scope: Are you planning to use the data for device registration elsewhere? The FDA for example indicates to accept OUS clinical data for medical device applications, but is looking for effectiveness data rather than performance. So in case you are considering using the data collected in Europe to support your product approval in the US, you better take that into account.

Conclusion

Summarizing, in Europe there is a clear trend towards higher clinical evidence demands: Clinical definitions are more comprehensive, clinical evaluations require more and better substantiation throughout the medical device life cycle, and the regulatory environment is becoming more strict including any type of clinical study. Since clinical trials are an expensive, time absorbing, but also a responsible activity, their planning, development, and execution should be done with even more care than before.

Please feel free reaching out in case you want to discuss the above or need any support for your medical device study.

The European Regulatory environment regarding clinical evaluations and clinical investigations shows a clear trend towards higher standards of evidence for medical devices with Revision 4 of the MEDDEV 2.7/1 and the upcoming MDR. ISO 14155 or any equivalent GCP is becoming the standard for any clinical study, Pre- as well as Post-market, when planning on using the collected data for support of device safety or performance. More-over, the clinical evaluation has become an ongoing process throughout the full product life cycle, will require manufacturer owned data, and will be needed for all medical device classes. This is very much in line with the developments in the mutual acceptance of foreign clinical data as I previously blogged about, and we see recent publications of guidelines in that respect from the FDA as well as the CFDA.

Do not hesitate reaching out to me in case of any questions or support needed in the collection of clinical evidence for your medical device.

It is hard to miss, but as of May 25, 2018, the GDPR becomes effective. Although collection and review of personal data and clinical studies have gone hand-in-hand for decades and therefore I do not expect major changes, the devil tends to be in the details, and I wanted to re-emphasize some key aspect in this post.

Scope

The definition of what is considered private data will be even wider than before under the and includes information where a person can be identified indirectly:

“’personal data’ means any information relating to an identified or identifiable natural person (‘data subject’); an identifiable natural person is one who can be identified, directly or indirectly, in particular by reference to an identifier such as a name, an identification number, location data, an online identifier or to one or more factors specific to the physical, physiological, genetic, mental, economic, cultural or social identity of that natural person”

The GDPR concerns data of all EU citizens, meaning that any ‘party’ collecting or processing (clinical study) data from an EU person is subject to it, also when they are based outside of the EU. In such cases it is essential that the Subject Information Letter/ Informed Consent contains clear wording regarding transfer of study data to third countries or international organizations that may have different/ less strict data-protection regulations. Mind you, that when the BREXIT becomes effective this likely includes UK-based companies.

Informed Consent

Ensuring proper Informed Consent is a standard widely acknowledged key process when running clinical studies, so most of the responsibilities defined by the GDPR are not new for those involved in it. It is worth mentioning though that the conditions have been strengthened, and most notable that besides being adequate, data collected need to be relevant and limited, and the purpose of data collection should be explicit at the time of data collection:

“The personal data should be adequate, relevant and limited to what is necessary for the purposes for which they are processed”, and

“… the specific purposes for which personal data are processed should be explicit and legitimate and determined at the time of the collection of the personal data.”.

So when a volunteer or patient signs the informed consent, it should be clear what data is being collected, for what purpose, and for how long it will be stored: Study sponsors and CRO’s must make sure they are only processing and storing the minimum amount of data required for the purpose consented to, and special attention is required for any purpose beyond the clinical trial such as use of collected data for training or future research (hardly explicit I think).

This implies that existing subject information letters and consent models require review and modification where needed for any clinical study moving forward to ensure compliance with the GDPR.

The question is whether participants of clinical studies that started before May 25 2018, need re-consenting? The current thinking seems to be that such is not required, but you may want to review your Informed Consent Forms for aspects as mentioned above, specifically data usage beyond the clinical study itself (training, any future research, …) and duration of data storage.

Roles and responsibilities

The GDPR is more specific regarding data controllers and processors and their responsibilities:

“‘controller’ means the natural or legal person, public authority, agency or other body which, alone or jointly with others, determines the purposes and means of the processing of personal data; where the purposes and means of such processing are determined by Union or Member State law, the controller or the specific criteria for its nomination may be provided for by Union or Member State law”, and

“‘processor’ means a natural or legal person, public authority, agency or other body which processes personal data on behalf of the controller”.

In other words, study sponsors (controllers), CRO’s, EDC providers, and Core Labs (processors) involved in clinical studies have their responsibilities spelled out in the GDPR. All should be aware of its content and possible implications, which means ensuring proper Informed Consent and tracking of the use and storage of the collected data throughout the clinical study accordingly.

Generally speaking responsibilities between the different ‘parties’ will be clear, but notably the GDPR includes a section regarding “joint controllers” (Article 26), so I think it is even more important that all parties involved, and mind you that includes freelancers, clearly define (and document) their roles for the clinical study at hand.

Of note in this respect is also that the study sponsor can also be an investigator: Investigator sponsored clinical studies are no exception nowadays and responsibilities are often blurred for such studies as mentioned in my earlier post on that topic. Therefore I think it is of essence that any investigator is aware of the implications the GDPR when running a clinical study where data is collected from EU citizens and (s)he has both the responsibilities of the sponsor and the investigator.

Conclusion

In conclusion, when dealing with clinical studies the impact of the GDPR is probably limited since we have been implementing the Informed Consent process for decades, but you need to take into consideration 1. a wider scope that includes any type of clinical data-collection, 2. an Informed Consent that needs to be even more explicit, with special attention for data-use beyond the study at hand, and 3. a better specification of the responsibilities of the study sponsor and data processors involved as the consequences in case of a personal data breach can be huge.

Please feel free to contact me in case you are interested in a more in depth discussion regarding the above or in case you are looking for any support with your medical device study.

There is no debate that under MEDDEV Rev 2.7/1 Rev. 4 and the MDR there is a higher demand for qualitative clinical evidence on medical device safety and performancebefore and after they are brought to market (also see my previous post on this topic). So medical device manufacturers with presence in the EU better timely evaluate their clinical evidence and seriously consider whether there is a need to start a clinical study now. When your evidence base is sufficient, you may not need to do so, and clinical studies are forever lasting, bureaucratic money-pits, but when your evidence does need strengthening, the latter is exactly the reason why you should initiate a clinical study at this very moment: Starting a clinical study now may give you just enough time to collect your own clinical data before the implementation of the MDR, and running a study in a postmarket setting is less costly and complex than in a premarket setting. Reasons why I think one cannot afford waiting any longer include but are not limited to:

Patient safety – PMCF

To minimize length and cost of premarket studies, patient follow-up in device studies is often limited to the bare minimum and shorter than the intended life-time of the device (imagine the length of a study with an implantable device that is supposed to function for the rest of your life …). Some device issues, however, may become only visible with wide spread and long term use, and following several scandals with implantable medical devices, the EU regulatory bodies, righteously so, became more strict on implementing the device directives with respect to their postmarket surveillance program, especially PMCF. So monitoring product safety in a postmarket setting as well as complying with the EU medical device directives is the number 1 reason to start your clinical study now. Number 2 is that

Clinical studies take time

Clinical project development from idea conception to the first-patient-In minimally takes 9 months: Yes, it is like a baby, you need half a year to come to agree on the design, develop the necessary documents, and then another 3 months to get the necessary regulatory approvals. Patient enrolment and follow-up, very much depending on the type of patient and device, will minimally last another 9 months (thus far I managed one project finishing enrolment several months ahead of plan). Data-cleaning, analysis, and reporting, depending on the size of the study, preparation, and internal procedures, will take at least another 4 months from last-patient-out to study report or abstract. This gives you a minimum of 22 months excluding long term patient follow-up and any delays, and brings us awfully close to the point in time when the MDR is applicable …. A third reason to start your clinical study sooner rather than later concerns the

Clinical study budget

When well thought through, medical device studies in a postmarket setting are less burdensome from regulatory perspective (less approvals, less paperwork, etc), and give more options for a more risk based approach. This makes this type of study more flexible, and – when well run – quicker and less costly. Bringing me to the last but definitely not the least reason to start your clinical study now, and that is

Clinical data access

Under MEDDEV 2.7/1 Rev. 4 and the MDR, it will be much harder to show that your device meets the essential requirements based on equivalence, and if one wants to pursue that clinical strategy one can only use clinical data that conform with the MDD/ MDR and when as a manufacturer you have access to

“… the data relating to devices with which they are claiming equivalence…”,

in other words, you basically need to create your own data-set or have a strong business relationship with the owner of the equivalent device providing you access to their data.

Conclusion

In conclusion, there are multiple reasons to stay away from running a clinical trial, but even more so to start one now. Especially when you are dealing with higher class and implantable devices, when your clinical evidence is in-complete and/ or not according to the regulatory requirements. In such case you cannot afford to wait any longer and to my opinion should start a clinical study as soon as possible.

Please feel free to reach out to me in person or via Applied Clinical Services in case you want to discuss any of the above or are looking for advice or support with your clinical evaluation process or clinical study.

The EU Medical Device Regulation (MDR) and the In Vitro Diagnostic device Regulation (IVDR) entered into force, local governments published guidance how to deal with the new medical device regulations, there is debate on the implementation of the MEDDEV 2.7/1 Rev. 4, and yet the number of posts from my end in 2017 have been minimal. I am afraid this is only symptomatic of what is happening in the clinical environment of medical devices in Europe: the demand for qualitative and manufacturer owned clinical evidence is rising, and medical device companies have only 2 years left to perform a gap analyses AND to address any gaps in their clinical data.

In short, one can only conclude that 2017 has been an exciting year for medical devices reflecting an environment of change with more firework to come, especially when looking at it from clinical evidence perspective: Changes that concentrate around a more thorough (premarket) clinical evaluation (refering to my previous blog post on that topic) with a more solid clinical evidence base, and a better, stricter postmarket surveillance program that includes Postmarket Clinical Follow-up studies. Medical devices companies better prepare themselves, and if not started at this point in time, perform a clinical evidence gap analysis and start collecting their own clinical data where needed NOW!

Please feel free reaching out in case of any questions regarding this post, or when you are looking for support with your medical device clinical evidence strategy.

Who is this blogger?

My name is Annet Muetstege and I am a clinical research expert, based in The Netherlands, with over 25 years of experience in all aspects of clinical evidence planning and execution especially in medical devices. I am the co-founder of Applied Clinical Services.